Process for Preparing 3,6-Dihydro-1,3,5-Triazine Derivatives

ABSTRACT

A process for the synthesis of 3,6-dihydro-1,3,5-triazine derivatives is claimed wherein a biguanid is reacted with acetaldehyde in the presence of an inorganic and/or organic base. The process can be carried out at mild and therefore economical reaction conditions.

The present invention relates to a process for the preparation of3,6-dihydro-1,3,5-triazine derivatives, wherein a biguanide is reactedwith an acetaldehyde in the presence of an inorganic and/or organicbase.

3,6-Dihydro-1,3,5-triazine derivatives show pharmacological propertiesin the treatment of pathological conditions associated with theinsulin-resistance syndrome. Several patents describe the preparation of3,6-dihydro-1,3,5-triazine derivatives. For example, in U.S. Pat. No.3,287,366 the synthesis of dihydro-triazine bearing the followingstructure is described:

The synthesis involves the reaction of a mono-substituted bisguanidineand an aldehyde or ketone in presence of an acid at elevatedtemperatures.

Japanese patent JP48064088 describes the synthesis of dihydro-triazinesbearing the following structure:

The analogous synthesis also involves heating under acidic condition.

Japanese patent JP54014986 describes the synthesis of dihydro-triazinesbearing the following structure:

Similarly, this method requires heating under acidic conditions.

Patent application WO 01/55122 describes the synthesis ofdihydro-triazines of the following structure:

The synthesis is directed to the reaction of mono-substitutedbisguanidines and an acetal, hemiacetal, ketal, hemiketal, aldehyde, orketone in presence of an acid at elevated temperatures.

Common to the published procedures is the requirement of elevatedtemperature, which may require refluxing conditions or high pressure iflow boiling point starting materials are employed as well as the use ofan acid The invention had the object of finding a reaction at roomtemperature under normal pressure and without reflux conditions whileonly inexpensive starting materials are used. This would save energy andimprove the safety of the process.

Unexpectedly, it has been found, that compounds of formula I can beprepared in presence of a base at room temperature under ambientpressure.

The invention relates to a process for the preparation of compounds ofthe formula I

in which

R¹, R², R³ and R⁴ are chosen independently from the following groups:

H;

C₁-C₂₀-alkyl optionally substituted by halogen, C₁-C₅-alkyl,C₁-C₅-alkoxy or C₃-C₈-cycloalkyl;

C₂-C₂₀-alkenyl optionally substituted by halogen, C₁-C₅-alkyl orC₁-C₅-alkoxy; C₂-C₂₀-alkynyl optionally substituted by halogen,C₁-C₅-alkyl or C₁-C₅-alkoxy; C₃-C₈-cycloalkyl optionally substituted byC₁-C₅-alkyl or C₁-C₅-alkoxy; C₃-C₈-heterocycloalkyl having one or morehetero atoms chosen from N, O and S and optionally substituted byC₁-C₅-alkyl or C₁-C₅-alkoxy;

C₆-C₁₄-aryl-(C₁-C₂₀)alkyl optionally substituted by amino, hydroxyl,thio, halogen, C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio,C₁-C₅-alkylamino, C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl, C₁-C₅-alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl;

C₆-C₁₄-aryl optionally substituted by amino, hydroxyl, thio, halogen,C₁-C₅-alkyl, C₁-C₅-alkoxy;

C₁-C₁₃-heteroaryl having one or more hetero atoms chosen from N, O and Sand optionally substituted by amino, hydroxyl, thio, halogen,C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-alkylamino,C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl;

R¹ and R², on the one hand, and R³ and R⁴, on the other hand, possiblyforming with the nitrogen atom an n-membered ring (n between 3 and 8)optionally comprising one or more hetero atoms chosen from N, O and Sand possibly being substituted by one of the following groups: amino,hydroxyl, thio, halogen, C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio,C₁-C₅-alkylamino, C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl;

R⁵ is chosen from the following groups:

C₁-C₂₀-alkyl optionally substituted by amino, hydroxyl, thio, halogen,C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-alkylamino,C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅-)-alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl;

C₂-C₂₀-alkenyl optionally substituted by amino, hydroxyl, thio, halogen,C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-alkylamino,C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl;

C₂-C₂₀-alkynyl optionally substituted by amino, hydroxyl, thio, halogen,C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-alkylamino,C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl;

C₃-C₈-cycloalkyl optionally substituted by amino, hydroxyl, thio,halogen, C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-alkylamino,C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl;

C₃-C₈-heterocycloalkyl having one or more hetero atoms chosen from N, Oand S and optionally substituted by amino, hydroxyl, thio, halogen,C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-alkylamino,C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl;

C₆-C₁₄-aryl optionally substituted by amino, hydroxyl, thio, halogen,C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-alkylamino,C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl;

C₁-C₁₃-heteroaryl having one or more hetero atoms chosen from N, O and Sand optionally substituted by amino, hydroxyl, thio, halogen,C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-alkylamino,C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl;

C₆-C₁₄-aryl-(C₁-C₅)-alkyl optionally substituted by amino, hydroxyl,thio, halogen, C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio,C₁-C₅-alkylamino, C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

and pharmaceutically usable derivatives, solvates, salts andstereoisomers thereof, characterised in that a compound of the formulaII

in which R¹, R², R³, R⁴ are as defined above,is reacted with a compound of the formula III

R⁵—CHO   III

in which R⁵ is as defined above,in a polar solvent or solvant mixture in presence of an anorganic and/ororganic base.

The base may be chosen from inorganic bases such as alkali hydroxides,alkali carbonates and alkali alcoholates, for example lithium hydroxide,sodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate, sodium methanolate, sodium ethanolate, etc. or organic basessuch as triethyl amine, diisopropylethyl amine, pyridine, pyrrol,pyrrolidine, piperidine, etc. and any mixtures of the above. With regardto the yield good results may be obtained with strong basids, inparticular alkali hydroxides etc., whereas sodium hydroxide ispreferred.

The process can be carried out in a solvent. Preferably, this is used inan amount that the reaction mixture can be stirred. The solvent may bechosen from from a wide variety of solvents which does not affect thereaction adversely such as Water, methanol, ethanol, isopropanol,n-butanol, 2-butanol, i-butanol, t-butanol and N,N-dimethyl formamideetc. or any mixtures of the solvents mentioned. Particularly suitablesolvents are water, alcohols and mixtures of water and alcohols, such asa mixture of water and methanol.

For carrying out the reaction it is advantageous in case the compound ofthe formula II and of the formula III are present in equimolar amountsup to an excess of the compounds of the formula III based on thecompound with the formula II. In a preferred embodiment, theconcentration of the compound of formula III ranges from 1 equivalent to10 equivalents to the compound of formula II.

The amount of base added may vary in wide ranges. Preferably, the amountof the base ranges from 0.5 equivalents to 10 equivalents, particularfrom 0.8 to 2 equivalents, with reference to the compound of the formulaII. In a preferred embodiment, the base is used in equimolar amountswith reference to the compound of formula II.

The term “solvates of the compounds” is taken to mean adductions ofinert solvent molecules onto the compounds which form owing to theirmutual attractive force. Solvates are, for example, mono- or dihydratesor alcoholates.

The term “pharmaceutically usable derivatives” is taken to mean, forexample, the salts of the compounds according to the invention andso-called prodrug compounds. The term “prodrug derivatives” is taken tomean compounds of the formula I which have been modified with, forexample, alkyl or acyl groups, sugars or oligopeptides and which arerapidly cleaved in the organism to form the active compounds accordingto the invention. These also include biodegradable polymer derivativesof the compounds according to the invention, as described, for example,in Int. J. Pharm. 115, 61-67 (1995).

Isomers of the compounds of formula I are intend to mean thestereoisomers and the tautomers.

The inventive reaction has the advantageous that it can be carried outat ambient pressure. The reaction temperature may vary from temperaturesof −10° C. up to temperatures of 100° C. In preferred embodiment thereaction is carried out at room temperature. In case weak bases areused, it may be advantageous to carry out the reaction at highertemperatures.

For all radicals which occur more than once, such as, for example, alkylor optional substituents on aryl or heterocyclic residues, theirmeanings are independent of one another.

Alkyl is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. Alkylis preferably methyl, furthermore ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl,-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, furthermorepreferably, for example, trifluoromethyl.

Alkyl is very particularly preferably alkyl having 1, 2, 3, 4, 5 or 6carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl,pentafluoroethyl or 1,1,1-trifluoroethyl.

Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl. Alkylene is preferably methylene, ethylene,propylene, butylene, pentylene or hexylene, furthermore branchedalkylene.

Alkenyl is preferably vinyl.

Alkynyl is preferably C≡CH.

Halogen is F, Cl, Br or I.

Alkoxy is preferably methoxy, ethoxy, propoxy or butoxy.

C₃-C₈-Heterocycloalkyl having one or more hetero atoms chosen from N, Oand S preferably is 2,3-dihydro-2-, -3-, -4- or -5-furyl,2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl,1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-,-3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2-or -4-imidazolyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or-4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl,1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxaneyl, 1,3-dioxane-2-, -4- or -5-yl, hexahydro-1-,-3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2-or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl.

Optionally substituted is meant to be unsubstituted or mono-, di-, tri-,tetra- or pentasubstituted.

Aryl preferably is phenyl, naphthyl or biphenyl.

Aryl alkyl preferably is benzyl.

Heteroaryl having one or more hetero atoms chosen from N, O and Spreferably is 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-,2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl,3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl,2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, furthermore preferably1,3-benzodioxol-5-yl, 1,4-benzodioxane-6-yl, 2,1,3-benzothiadiazol-4- or-5-yl or 2,1,3-benzoxadiazol-5-yl.

R¹, R², R³ and R⁴ preferably are chosen independently from the followinggroups:

C₁-C₂₀-alkyl optionally substituted by halogen, C₁-C₅-alkyl,C₁-C₅-alkoxy or C₃-C₈-cycloalkyl;

C₂-C₂₀-alkenyl optionally substituted by halogen, C₁-C₅-alkyl orC₁-C₅-alkoxy;

C₂-C₂₀-alkynyl optionally substituted by halogen, C₁-C₅-alkyl orC₁-C₅-alkoxy;

C₃-C₈-cycloalkyl optionally substituted by C₁-C₅-alkyl or C₁-C₅-alkoxy;

C₃-C₈-heterocycloalkyl having one or more hetero atoms chosen from N, Oand S and optionally substituted by C₁-C₅-alkyl or C₁-C₅-alkoxy;

C₆-C₁₄-aryl-(C₁-C₂₀)-alkyl optionally substituted by amino, hydroxyl,thio, halogen, C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio,C₁-C₅-alkylamino, C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl;

C₆-C₁₄-aryl optionally substituted by amino, hydroxyl, thio, halogen,C₁-C₅-alkyl, C₁-C₅-alkoxy;

C₁-C₁₃-heteroaryl having one or more hetero atoms chosen from N, O and Sand optionally substituted by amino, hydroxyl, thio, halogen,C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-alkylamino,C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl;

R¹ and R², on the one hand, and R³ and R⁴, on the other hand, possiblyforming with the nitrogen atom an n-membered ring (n between 3 and 8)optionally comprising one or more hetero atoms chosen from N, O and Sand possibly being substituted by one of the following groups: amino,hydroxyl, thio, halogen, C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio,C₁-C₅-alkylamino, C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl.

A preferred process for the preparation of compounds of formula I isrelated to compounds in which

R¹, R² are independently from each other C₁-C₂₀-alkyl;

R³, R⁴ are H;

R⁵ is C₁-C₂₀-alkyl.

A particularly preferred process for the preparation of compounds offormula I is related to compounds

in which

R¹, R² are independently from each other C₁-C₅-alkyl;

R³, R⁴ are H;

R⁵ is C₁-C₆-alkyl.

Most particularly preferred is a process for the preparation of acompound of formula I in which

R¹, R² are methyl;

R³, R⁴ are H;

R⁵ is methyl.

There is an example giving further detail on the invention, but theinvention is not limited within the example.

EXAMPLE 1 Preparation of2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine

A 4 L two neck flask charged with 662 g (4 mol) metformin HCl and 1600mL MeOH was stirred with a magnetic bar at 750 rpm at room temperaturewith a water bath. To this suspension was added sodium hydroxide 160 g(4 mol) in 200 mL water through one dropping funnel. At the same timeacetaldehyde 226 mL (4 mol) in 400 mL of MeOH in another funnel wasadded to the mixture. The addition of NaOH solution finished in 70minutes whereas the addition of acetaldehyde finished in 100 minutes.Then, the reaction mixture was filtered through celite to remove thesodium chloride. The solution was concentrated to give a white solidthat was extracted with 1.2 L of hot ethanol to give a suspension. Afterfiltration, the ethanol solution was concentrated to give a pale yellowsolid, 520 g, yield is 84%.

¹H NMR (300 MHz, CDCl₃) δ 1.37 (d, J=6.0 Hz, 3H), 2.98 (s, 6H), 3.46 (s,1H), 4.83 (q, J=6.0 Hz, 1H). ¹³C NMR (300 MHz, CDCl₃) δ 24.5, 36.4,63.0.

EXAMPLE 2

To a suspension of metfomin HCl 1.65 g (10 mmol) and sodium hydroxide0.4 g (10 mmol) on 10 mL methanol was added a solution of acetaldehyde0.56 mL (10 mmol) in 4 mL methanol at room temperature during 10minutes, followed by stirring for 1 hour. Then the solution was filteredand concentrated to give white solid. The white solid was dissolved in10 mL hot ethanol and filtered again. After concentration under vacuum,1.4 g white solid with obtained, yield: 90%.

EXAMPLE 3

To a solution of metformin HCl 1.65 g (10 mmol) and sodium hydroxide 0.4g (10 mmol) in 10 mL water was added a solution of acetaldehyde 0.56 mL(10 mmol) in 4 mL water during 10 minutes. After 1 hour at roomtemperature. The solution was concentrated to give white solid. Then thesolid was dissolved in 10 mL ethanol and filtered. After concentration,1.45 g white solid was achieved, yield 93%.

1. A process for preparing a compound of formula I:

in which R¹, R², R³ and R⁴ are chosen independently from the followinggroups: H; C₁-C₂₀-alkyl optionally substituted by halogen, C₁-C₅-alkyl,C₁-C₅-alkoxy or C₃-C₈-cycloalkyl; C₂-C₂₀-alkenyl optionally substitutedby halogen, C₁-C₅-alkyl or C₁-C₅-alkoxy; C₂-C₂₀-alkynyl optionallysubstituted by halogen, C₁-C₅-alkyl or C₁-C₅-alkoxy; C₃-C₈-cycloalkyloptionally substituted by C₁-C₅-alkyl or C₁-C₅-alkoxy;C₃-C₈-heterocycloalkyl having one or more hetero atoms chosen from N, Oand S and optionally substituted by C₁-C₅-alkyl or C₁-C₅-alkoxy;C₆-C₁₄-aryl-(C₁-C₂₀)alkyl optionally substituted by amino, hydroxyl,mercapto, halogen, C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio,C₁-C₅-alkylamino, C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl, C₁-C₅-alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; C₆-C₁₄-aryloptionally substituted by amino, hydroxyl, mercapto, halogen,C₁-C₅-alkyl, C₁-C₅-alkoxy; C₁-C₁₃-heteroaryl having one or more heteroatoms chosen from N, O and S and optionally substituted by amino,hydroxyl, mercapto; halogen, C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio,C₁-C₅-alkylamino, C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; R¹ and R², onthe one hand, and R³ and R⁴, on the other hand, possibly forming withthe nitrogen atom an n-membered ring (n between 3 and 8) optionallycomprising one or more hetero atoms chosen from N, O and S and possiblybeing substituted by one of the following groups: amino, hydroxyl,mercapto, halogen, C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio,C₁-C₅-alkylamino, C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; R⁵ is chosenfrom the following groups: C₁-C₂₀-alkyl optionally substituted by amino,hydroxyl, mercapto, halogen, C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio,C₁-C₅-alkylamino, C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅-)-alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; C₂-C₂₀-alkenyloptionally substituted by amino, hydroxyl, mercapto, halogen,C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-alkylamino,C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl; C₂-C₂₀-alkynyl optionallysubstituted by amino, hydroxyl, mercapto, halogen, C₁-C₅-alkyl,C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-alkylamino, C₆-C₁₄-aryl-oxy,C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano, trifluoromethyl, carboxyl,carboxymethyl or carboxyethyl; C₃-C₈-cycloalkyl optionally substitutedby amino, hydroxyl, mercapto, halogen, C₁-C₅-alkyl, C₁-C₅-alkoxy,C₁-C₅-alkylthio, C₁-C₅-alkylamino, C₆-C₁₄-aryl-oxy,C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano, trifluoromethyl, carboxyl,carboxymethyl or carboxyethyl; C₃-C₈-heterocycloalkyl having one or morehetero atoms chosen from N, O and S and optionally substituted by amino,hydroxyl, mercapto, halogen, C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio,C₁-C₅-alkylamino, C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl; C₆-C₁₄-aryloptionally substituted by amino, hydroxyl, mercapto, halogen,C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-alkylamino,C₆-C₁₄-aryl-oxy, C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl; C₁-C₁₃-heteroaryl having one ormore hetero atoms chosen from N, O and S and optionally substituted byamino, hydroxyl, mercapto, halogen, C₁-C₅-alkyl, C₁-C₅-alkoxy,C₁-C₅-alkylthio, C₁-C₅-alkylamino, C₆-C₁₄-aryl-oxy,C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano, trifluoromethyl, carboxyl,carboxymethyl or carboxyethyl; C₆-C₁₄-aryl-(C₁-C₅)-alkyl optionallysubstituted by amino, hydroxyl, mercapto, halogen, C₁-C₅-alkyl,C₁-C₅-alkoxy, C₁-C₅-alkylthio, C₁-C₅-alkylamino, C₆-C₁₄-aryl-oxy,C₆-C₁₄-aryl-(C₁-C₅)-alkoxy, cyano, trifluoromethyl, carboxyl,carboxymethyl or carboxyethyl, or a pharmaceutically usable derivative,solvate, salt or stereoisomer thereof, said process comprising reactinga compound of the formula II:

in which R¹, R², R³, R⁴ are as defined above, with a compound of theformula III:R⁵—CHO   III in which R⁵ is as defined above, in a polar solvent orsolvant mixture in presence of an inorganic and/or organic base. 2.Process according to claim 1, in which R¹, R² are independently fromeach other C₁-C₂₀-alkyl; R³ and R⁴ are H; and R⁵ is C₁-C₂₀-alkyl(C1-C20).
 3. Process according to claim 1, in which R¹, R² areindependently C₁-C₆-alkyl; R³ and R⁴ are H; and R⁵ is C₁-C₆-alkyl. 4.Process according to claim 1, in which R¹ and R² are methyl; R³ and R⁴are H and R⁵ is methyl.
 5. Process according to claim 1, in which thebase is chosen from alkali hydroxides, alkali carbonates and alkalialcoholates or organic bases chosen from triethyl amine,diisopropylethyl amine, pyridine, pyrrol, pyrrolidine, and piperidine,and any mixtures thereof.
 6. Process according to claim 1, in which thesolvent is chosen from water, methanol, ethanol, isopropanol, n-butanol,2-butanol, i-butanol, t-butanol, N,N-dimethyl formamide and any mixturesthereof.
 7. Process according to claim 1, in which the concentration ofcompound of formula III is from 1 equivalent to 10 equivalents based onthe compound of the formula II.
 8. Process according to claim 1, inwhich the base is present in an amount from 0.5 equivalents to 10equivalents based on the compound of formula II.
 9. Process accordingclaim 1, in which the compound of formula III is acetaldehyde. 10.Process according to claim 1, in which the reaction is performed underambient pressure.
 11. Process according to claim 1, in which thereaction is performed at room temperature.